At present, molecular targeted therapy has been widely developed, targeting driver oncogenes (essential proto-oncogenes). The driver oncogene is a proto-oncogene having a genetic mutation that is considered to cause a mutation (e.g., point mutation, small deletion, insertion or translocation, amplification, etc.) specific to cancer cells and to become a main cause of cancer development. Accordingly, a technique of developing a drug that targets such a driver oncogene and suppresses the function thereof has been demonstrated to be a method extremely effective for the development of a specific remedy for cancer patients. Examples of such a specific remedy include: Iressa exhibiting drastic effectiveness for lung cancer patients with mutated EGFR; Trastuzumab effective for patients with breast cancer derived from high expression of HER2; and Imatinib that is an activity inhibitor for the fusion protein BCR-ABL.
The genetic mutations of such driver oncogenes are divided into two types; namely, (1) changes in gene sequences (point mutation, chromosomal translocation, deletion and/or insertion) (or such deletion or translocation mutation includes a mutation, in which SNP (single nucleotide polymorphism) becomes monoallelic or homoallelic in tumor cells, although it becomes heteroallelic in normal cells); and (2) changes in gene copy numbers (i.e., increases in gene expressions). As driver oncogenes having the above mutation (1), RAS, KRAS, HRAS, NRAS, BCR-ABL, EGFR, c-KIT, BRAF, PI3K, ALK, PIK3CA, FLT3, MET, BCL2, EML4-ALK, APC, BRCA1/2, TP53, MSH2, MLH1, MSH6, PMS2, RB1, PIEN, VHL, P16, MEN1, RET, CDH1, STK11, and PTCH have been known. As driver oncogenes having the above mutation (2), Her2/neu, EGFR, MYC, MYCN, MET, etc. have been known. Other driver oncogenes have been registered in cancer gene mutation database (COSMIC [Catalogue of somatic mutations in cancer], etc).
To date, the development of drugs that specifically target the mutated sites of driver oncogene products has been frequently carried out. However, such a drug may also suppress the function of a normal gene product needed by normal cells, and a drug of interest has not yet been developed under the current circumstances.
It has been reported that pyrrole-imidazole polyamide (PIP) is an artificial small molecule developed using the antibiotic distamycin as a motif, and that PIP sequence-specifically binds to a minor group of double-stranded DNA. There have been many reports on studies regarding suppression of the gene expression of a target sequence by PIP. Moreover, the use of PIP as a drug candidate used for renal impairment, an anticancer agent, or a therapeutic agent for corneal injury, hyperplastic scar, bone disease, etc. has been studied based on animal experiments using mice. Furthermore, in recent years, also in the study of iCeMs, which is an iPS cell project conducted by Kyoto University as a part of studies regarding iPS cells, induction of iPS cells by PIP has been studied. Thus, PIP is an organic small molecule, regarding which various successful study results are expected.
Examples of the characteristics of PIP include: (1) possible designing of PIP, targeting any given gene sequence; (2) the binding ability of PIP to DNA, which is stronger than that of a transcriptional factor; (3) incorporation of PIP into the nucleus of a cell, without using vectors or drug delivery systems (DDS); (4) PIP, which is not decomposed by nucleic acid-decomposing enzyme, is stable in cells or living bodies, and is discharged as an undecomposed product from urine and/or bile; and (5) the N- and C-termini of PIP, which can be easily modified, so that PIP is able to form a complex with various functional small molecules.
In PIP, the Py/Im pair recognizes CG, the Py/Py pair recognizes AT or TA, and the Im/Py pair recognizes GC, so that the PIP is able to sequence-specifically bind to various any given double-stranded DNAs. PIP that binds to a target gene has been studied as a gene switch that inhibits the binding of a transcription factor to DNA and suppresses a specific gene expression.
Utilizing a PIP structure having high sequence recognition specificity, the present inventor had synthesized a complex of an alkylating functional group and PIP, and had succeeded in completing an invention relating to an indole derivative alkylating a specific nucleotide sequence of DNA (Patent Literature 2), and also, the inventor had synthesized a complex of a histone modification regulator and PIP, and had succeeded in completing an invention relating to a target gene-specific histone modification regulator (Patent Literature 1). However, it has not yet been reported that a drug, which targets the driver mutation of a driver oncogene (i.e., a genetic mutation that becomes a main cause of inducing cancer), has been synthesized based on the concept that is the use of PIP, and that the tumor-suppressing effect of the synthesized drug has been actually confirmed.